The present invention relates to the use of GABA-B selective agonists in treating cough in mammals.
Gamma amino butryic acid (GABA) is a ubiquitous inhibitory neurotransmitter in the CNS and peripheral nervous systems (F. E. Bloom. Neurohumoral Transmission and the central nervous system. The Pharmacological Basis of Therapeutics, 7th Ed. (A. G. Gilman, L. S. Goodman, T. W. Rall and F. Murad, eds), MacMillan Publishing, N.Y., 1985, p. 250.). Evidence strongly suggests that GABA mediates the inhibitory actions of local interneurons in the brain and also mediates presynaptic inhibitory effects within the spinal cord. GABA appears to bind to at least two distinct types of receptors. Of these, GABA-A receptors have been well characterized and are coupled to chloride channels (J. Bormann. Electrophysiology of GABA-A and GABA-B receptor subtypes. Trends Neurosci., 11, 112-116, 1988.). It is to these GABA-A receptors that benzodiazepines bind and exert anticonvulsant and anxiolytic effects through a facilitation of the action of GABA (E. Costa. Polytypic signalling at GABAergic synapses. Life Sci., 42, 1407-1417, 1988.). These receptors can be selectively blocked with convulsant agents such as bicuculline. In contrast, GABA-B receptors are less well understood, although baclofen is a specific agonist at these bicuculline-insensitive receptors (N. Bowery. GABA-B receptors and their significance in mammalian pharmacology. TIPS Revies, 10, 401-407, 1989, and N. G. Bowery, A. Doble, D. R. Hill, A. L. Hudson, J. S. Shaw, M. J. Turnball and R. Warrington. Bicuculline-insensitive GABA receptor on peripheral autonomic nerve terminals. Eur. J. Pharmac., 71, 53-70, 1981.). It now appears that GABA-B receptors are coupled to either calcium or potassium channels (J. Bormann. Electrophysiology of GABA-A and GABA-B receptor subtypes. Trends Neurosci., 11, 112-116, 1988.).
GABA-B selective agents may not elicit the side effects associated with selective or non-selective activation of GABA-A receptors. For example, benzodiazepines facilitate responses at GABA-A receptors and produce troublesome side-effects of motor-incoordination, confusion, light-headedness and other adverse psychomotor and psychological effects (S. C. Harvey. Hypnotics and sedatives. The Pharmacological Basis of Therapeutics, 7th Ed. (A. G. Gilman, L. S. Goodman, T. W. Rall and F. Murad, eds), MacMillan Publishing, N.Y., 1985, pp. 349-350.).
Nosalova et al. recently described an antitussive effect for gabalinoleamide, a non-selective agonist at GABA receptors (G. Nosalova, D. Varonos, Z. Papadopoulou-Daipotis, P. Visnovsky and A. Strapkova. GABAergic mechanisms in the central control of cough. Acta Physiologica Hungarica, 70, 189-194, 1987.). They relate the antitussive and respiratory depressant effect of gabalinoleamide to an action at GABA-A receptors because similar effects are mentioned with respect to muscimol, a selective GABA-A agonist.